The basal ganglia and motor thalamic nuclei are functionally and anatomically divided into the sensorimotor, supplementary motor, premotor, associative and limbic territories. There exist both primary segregated basal ganglia-thalamocortical loops and convergence of functionally related information from different cortical areas onto these cortical basal ganglia-thalamocortical loops. The basal ganglia-thalamocortical loop arising from the sensorimotor area, supplementary motor area (SMA), premotor area and cingulate motor area provides distinct segregated subloops through the functionally distinct striatal, pallidal and thalamic regions with partial overlap. The subthalamic nucleus (STN) is also topographically organized. The ventrolateral part of the caudal 2/3 levels of the medial pallidal segment (GPi) projects to the primary motor area via the oral part of the ventral lateral thalamic nucleus (VLo) (Voa, Vop by Hassler's nomenclature). The thalamic relay nuclei of the GPi projection to SMA are identified in the transitional zone of the VApc (parvicellular part of the anterior ventral nucleus)-VLo and in the rostromedial part of the VLo. The thalamic nuclei relaying the cingulate subloop are not yet clearly defined. The supplementary motor subloop appears to be divided into the pre-SMA and SMA proper subloops. The premotor area is also divided into the dorsal premotor area subloop and the ventral premotor area subloop. It is suggested that the limbic loop consists of a number of subloops in the monkey as indicated by Haber et al. and in rats. We review here the microcircuitry of the striatum, as well as the convergence and integration between the functionally segregated loops. Finally, we discuss the functional implications of striatal connections.

The nectin–afadin system is a novel cell–cell adhesion system that organizes adherens junctions cooperatively with the cadherin–catenin system in epithelial cells. Nectin is an immunoglobulin-like adhesion molecule, and afadin is an actin filament–binding protein that connects nectin to the actin cytoskeleton. Nectin has four isoforms (-1, -2, -3, and -4). Each nectin forms a homo-cis-dimer followed by formation of a homo-trans-dimer, but nectin-3 furthermore forms a hetero-trans-dimer with nectin-1 or -2, and the formation of each hetero-trans-dimer is stronger than that of each homo-trans-dimer. We show here that at the synapses between the mossy fiber terminals and dendrites of pyramidal cells in the CA3 area of adult mouse hippocampus, the nectin–afadin system colocalizes with the cadherin–catenin system, and nectin-1 and -3 asymmetrically localize at the pre- and postsynaptic sides of puncta adherentia junctions, respectively. During development, nectin-1 and -3 asymmetrically localize not only at puncta adherentia junctions but also at synaptic junctions. Inhibition of the nectin-based adhesion by an inhibitor of nectin-1 in cultured rat hippocampal neurons results in a decrease in synapse size and a concomitant increase in synapse number. These results indicate an important role of the nectin–afadin system in the formation of synapses.

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Synaptic scaffolding molecule (S-SCAM) interacts with a wide variety of molecules at excitatory and inhibitory synapses. It comprises three alternative splicing variants, S-SCAM␣, -␤, and -␥. We generated mutant mice lacking specifically S-SCAM␣. S-SCAM␣-deficient mice breathe and feed normally but die withinVarious scaffold proteins, such as PSD-95 and gephyrin, play an important role at excitatory and inhibitory synapses in the brain. The physiological importance of these proteins is underscored by the results of studies using mutant mice. PSD-95 mutant mice show impaired learning and lack of neuropathic sensitization (9, 28). Gephyrin-deficient mice fail to suckle and die within 1 day of birth (6). Glycine receptor clustering is disrupted in these mice. Synaptic scaffolding molecule (S-SCAM)/membrane-associated guanylate kinase inverted-2 (MAGI-2) was originally characterized as a scaffold protein interacting with N-methyl-D-aspartate (NMDA) receptors at excitatory synapses (16). The protein comprises a guanylate kinase domain, two WW domains, and PSD-95/Discs large/ Zonula Occludens-1 (PDZ) domains. S-SCAM interacts with various components of excitatory synapses (4). Moreover, we have recently reported that S-SCAM interacts with neuroligin 2 and ␤-dystroglycan at inhibitory synapses in rat hippocampal neurons (42). These interactions of S-SCAM with a wide variety of synaptic molecules lead us to speculate that S-SCAM plays an important role as a scaffold at both excitatory and inhibitory synapses. However, direct evidence that S-SCAM is a critical component of synapses is missing. To address this question, we generated mice lacking S-SCAM.The S-SCAM gene is located on human chromosome 7 and mouse chromosome 5. It spans more than 1.4 Mb. There are three alternative splicing variants, S-SCAM␣, -␤, and -␥, which start with different initiation methionines. S-SCAM␣ is the longest and has an additional N-terminal PDZ domain (17). S-SCAM␤ and -␥ start in the guanylate kinase domain. The exon coding the initiation methionine of S-SCAM␣ is separated by more than 1,000 kb from the first noncoding exon of S-SCAM␤. We replaced the first exon of the coding region of S-SCAM␣ with a neomycin resistance (neo R ) gene cassette

Previously we reported that AMAP2/PAG3/Pap␣/ KIAA0400, a GTPase-activating protein (GAP), acts to antagonize Arf6 function when overexpressed, whereas it was shown to exhibit efficient GAP activities for other Arf isoforms in vitro. Here, we found that AMAP2, through its ArfGAP domain, binds to GTP-Arf6 but not to GDP-Arf6 or other Arfs irrespective of nucleotide status. The majority of AMAP2 was localized to intracellular tubulovesicular structures and redistributed to Arf6-enriched membrane areas upon Arf6 activation. In HeLa cells, Arf6 has been shown to be involved in the clathrinindependent endocytosis of Tac, but not the clathrin-dependent endocytosis of transferrin. We found that Arf6 silencing inhibited the internalization of Tac, but not transferrin, in HeLa cells. Internalization of Tac, but not transferrin, was also significantly inhibited by AMAP2 silencing and overexpression. AMAP2 was moreover found to bind to amphiphysin IIm, a component of the endocytic machinery, via its proline-rich domain. We propose that AMAP2 has dual mechanisms for its function; it exhibits efficient catalytic GAP activity for the class I and II Arfs and yet is involved in the cellular function of the class III Arf without immediate GAP activity. These dual mechanisms of AMAP2 may be important for the cellular function of GTP-Arf6.